Quinine thiourea derivatives

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

Quite recently, we also observed that quinine-based thiourea derivatives showed dramatic concentration and temperature effects on the enantioselectivity in the alcoholytic desymmetrization ofmeso-cyclic anhydrides, which can also be attributed to the self-association of the catalyst [23]. Of course, the possibility that the variation in... 

Lattanzi et al. expanded the substrate scope to the less-reactive (3-keto-amides. Unmodified quinine and dihydroquinine were slightly more efficient than several other p-aminoalcohol catalysts, including quaternised alkaloid and thiourea derivatives (Scheme 15.23). ° However, acyclic p-ketoamides did not afford products under the same conditions. 

In 2009, Enders and Hoffman explored the reactivity of a,(3-unsaturated sulfonates and aromatic thiols in sulfa-Michael additions. When the reactions were catalysed by a chiral bifunctional thiourea derived from quinine, the sulfa-Michael adducts were formed in moderate enantioseleetivities of up to 64% ee, albeit with generally good yields, as shown in Seheme 1.70. 

Reactions of phosphonic acids and their derivatives A novel approach to cyclic phosphonates (296) has been developed via a quinine thiourea catalysed, enatioselective Michael addition of quaternary a-nitroallq lphosphonates (293) to enones (294). Selected nitrophos-phonates (295) have been conveniently transformed to the phosphonates (296) and (297) via in situ reduction-intramolecular cyclisation or Baeyer-Villiger oxidation followed by in situ reduction-intramolecular cyclisation, respectively (Scheme 99). ... 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Deng and coworkers also found that the bifunctional quinidine- or quinine-based thioureas 36 and 40 effectively catalyze the asymmetric Friedel-Crafts reaction of indoles with a variety of aromatic and alkyl-substituted aldimine derivatives 159. Both enantiomeric forms of the products 160 were obtained with uniformly high... 

Wang and coworkers found that the quinine-derived thiourea catalyst 81b (1 mol%) was also highly reactive and enantioselective for the tandem thio-Michael-aldol reaction of various 2-mercaptobenzaldehydes (103) with a,P-unsaturated oxazolidi-nones (104), furnishing benzothiopyranes (105) with three stereogenic centers in... 

A bifunctional iminiumyhydrogen-bonding catalysis has been very recently employed for the first enantioselective organocatalytic conjugate addition of a phosphorous nucleophile (diarylphosphane oxides) to a,ji-unsaturated ketones [370]. The process, which allows efficient additions to cyclic and linear enones as well as the generation of quaternary stereocenters, is catalyzed by quinine-derived thiourea... 

Regarding the hydroxylation of nitroolefins, the reaction is performed under hydrogen-bonding catalysis using quinine-derived thiourea 170 (5 mol%), ethyl glyoxylate oxime as nucleophile in toluene at -24°C [374], This process, which constitutes a valid alternative to the Henry reaction, yields the corresponding hydroxylated nitrocompounds in good yields (63-83%) and enantioselectivities (48-93% ee) from ahphatic electrophiles (styrene derivatives are prone to retio-Michael addition) and has been successfully employed in the synthesis of optically active P-amino alcohols (Scheme 2.132) [375]. 

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